Alpha-(Aryl-or Heteroaryl-Methyl)-Beta-Piperidino Propanamide Compounds as Orl-1-Receptor Antagonists

Abstract

This invention provides the compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 independently represent hydrogen or the like; R 3 and R 4 independently represents hydrogen or the like; R 5 represents aryl or the like; —X—Y— represents —CH 2 O— or the like; and n represents 0, 1 or 2. These compounds have ORL1-receptor antagonist activity; and therefore, are useful to treat diseases or conditions such as pain, various CNS diseases etc.

1 - 15 . (canceled) 
     
     
         16 . A compound of the following formula (I) 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently hydrogen, halogen, or (C 1 -C 3 )alkyl; 
         R 3  and R 4  are independently hydrogen, (C 3 -C 6 )cycloalkyl, or (C 1 -C 3 )alkyl each optionally substituted by 1 to 3 substituents each independently selected from halogen or hydroxy; 
         R 5  is aryl or heteroaryl, each optionally substituted by 1 to 3 substituents independently selected from halogen, hydroxy, (C 1 -C 3 )alkyl, or (C 1 -C 3 )alkoxy, wherein said heteroaryl is a 5- or 6-membered aromatic heterocyclic group comprising (a) 1 to 4 nitrogen atoms, (b) 1 oxygen or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen atoms, 
         —X—Y— is —CH 2 O—, —CH(CH 3 )O—, or —C(CH 3 ) 2 O—; 
         and n represents 0, 1 or 2; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         17 . The compound of  claim 16 , wherein R 3  and R 2  are independently hydrogen or fluorine; or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The compound of  claim 16 , wherein R 3  and R 4  are independently hydrogen or (C 1 -C 3 )alkyl optionally substituted by 1 to 3 substituents each independently selected from halogen or hydroxy; or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The compound of  claim 17 , wherein R 3  and R 4  are independently hydrogen or (C 1 -C 3 )alkyl optionally substituted by 1 to 3 substituents each independently selected from halogen or hydroxy; or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The compound of  claim 16 , wherein R 3  and R 4  are independently hydrogen or (C 1 -C 3 )alkyl; or a pharmaceutically acceptable salt thereof. 
     
     
         21 . The compound of  claim 17 , wherein R 3  and R 4  are independently hydrogen or (C 1 -C 3 )alkyl; or a pharmaceutically acceptable salt thereof. 
     
     
         22 . The compound of  claim 16 , wherein R 5  is phenyl or heteroaryl selected from pyridyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, isoxazolyl, or oxazolyl;
 said phenyl and heteroaryl are optionally substituted by 1 to 3 substituents each independently selected from fluorine, chlorine, hydroxy, or methyl; or a pharmaceutically acceptable salt thereof.   
     
     
         23 . The compound of  claim 17 , wherein R 5  is phenyl or heteroaryl selected from pyridyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, isoxazolyl, or oxazolyl;
 said phenyl and heteroaryl are optionally substituted by 1 to 3 substituents each independently selected from fluorine, chlorine, hydroxy, or methyl; or a pharmaceutically acceptable salt thereof.   
     
     
         24 . The compound of  claim 16 , wherein R 5  is thiazolyl, isothiazolyl, pyrazolyl, or imidazolyl; or a pharmaceutically acceptable salt thereof. 
     
     
         25 . The compound of  claim 17 , wherein R 5  is thiazolyl, isothiazolyl, pyrazolyl or imidazolyl; or a pharmaceutically acceptable salt thereof. 
     
     
         26 . The compound of  claim 21 , wherein R 5  is thiazolyl, isothiazolyl, pyrazolyl, or imidazolyl; or a pharmaceutically acceptable salt thereof. 
     
     
         27 . The compound of  claim 16 , wherein R 5  represents heteroaryl selected from thiazolyl or pyrazolyl; or a pharmaceutically acceptable salt thereof. 
     
     
         28 . The compound of  claim 16 , wherein —X—Y— is —CH 2 O—; or a pharmaceutically acceptable salt thereof. 
     
     
         29 . The compound of  claim 16 , wherein —X—Y— is —CH 2 O— and n is 0 or 1; or a pharmaceutically acceptable salt thereof. 
     
     
         30 . The compound of  claim 17 , wherein —X—Y—Y is —CH 2 O— and n is 0 or 1; or a pharmaceutically acceptable salt thereof. 
     
     
         31 . The compound of  claim 21 , wherein —X—Y— is —CH 2 O— and n is 0 or 1; or a pharmaceutically acceptable salt thereof. 
     
     
         32 . The compound of  claim 26 : wherein —X—Y— is —CH 2 O— and n is 0 or 1; or a pharmaceutically acceptable salt thereof. 
     
     
         33 . The compound of  claim 16 , selected from: 
       N,N-Dimethyl-3-(3′H, 8H-spiro[8-azabicylo[3.2.1]octane-3,1′-[2]benzofuran]-8-yl)-2-(1,3-thiazol-4-ylmethyl)propanamide; 
       N,N-Dimethyl-3-(1H-pyrazol-1-yl)-2-(3H: 8H-spiro[8-azabicyclo[3.2, 1]octane-3,1-[2]benzofuran]-8-ylmethyl)propanamide 
       (+)—N,N-dimethyl-3-(1H-pyrazol-1-yl)-2-(3H,8H-spiro[8-azabicyco[3.2.1]octane-3,1′-[2]benzofuran]-8-ylmethyl)propanamide; 
       (−)-N,N-dimethyl-3-(1H-pyrazol-1-yl)-2-(3′H,8H-spiro[8-azabicyclo[3.2.1]octane-3,1′-[2]benzofuran]-8-ylmethyl)propanamide 
       3-(6′-Fluoro-3′H,8H-spiro[8-azabicyclo[3.2.1]octane-3,1′-[2]benzofuran]-8-yl)-N,N-dimethyl-2-(1H-pyrazol-1-ylmethyl)propanamide; 
       (+)-3-(6′-Fluoro-3′H,8H-spiro[8-azabicyclo[3.2.1]octane-3,1′-[2]benzofuran]-8-yl)N,N-dimethyl-2-(1H-pyrazol-1-ylmethyl)propanamide; 
       (−)-3-(6′-Fluoro-3′H,8H-spiro[8-azabicylo[3.2.1]octane-3, 1′-[ ]benzofuran]-8-yl)-N,N-dimethyl-2-(1H-pyrazol-1-ylmethyl)propanamide; 
       3-(6′-Fluoro-3′H,8H-spiro[8-azabicyclo[3.2.1]octane-3,1-[2]benzofuran]8-yl)N,N-dimethyl-2-(1H-pyrazol-1-ylmethyl)propanamide; 
       3-(6′-Fluoro-3′H,8H-spiro[8-azabicyclo[3.2.1]octane-3,1-′[2]Jbenzofuran]-8-yl)-N,N-dimethyl-2-(1,3-thiazol-4-ylmethyl)propanamide; 
       3-(3′,4′-Dihydro-8H-spiro[8-azabicyclo[3.2.1]octane-3,1′-isochromen]-8-yl)-N,N-dimethyl-2-(1H-pyrazol-1-ylmethyl)propanamide, 
       3-(6′-fluoro-3′,4′-dihydro-8H-spiro[8-azabicyclo[3.2.1]octane-3,1′-isochromen]-8-yl)-N,N-dimethyl-2-(1H-pyrazol-1-ylmethyl)propanamide; 
       (+)-3-6′-fluoro-3′ 4′-dihydro-8H-spiro[8-azabicyco[3.2.1]octane-3,1′-isochromen]-8-yl)-N: N-dimethyl-2-(1H-pyrazol-1-ylmethyl)propanamide; 
       (−)-3-(6′-fluoro-3′:4′-dihydro-8H-spiro[8-azabicyclo[3.2.1]octane-3,1′-isochromen]-8-yl)-N N-dimethyl-2-(1H-pyrazol-1-ylmethyl)propanamide;
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         34 . A pharmaceutical composition the compound of  claim 16  or a pharmaceutically salt thereof, together with at least one pharmaceutically acceptable excipient. 
     
     
         35 . A method of treating a disease for which an ORL1 antagonist is indicated comprising administering to a subject in need thereof an effective amount of the compound of  claim 16 , or a pharmaceutically salt thereof.